This research will define the mechanisms by which the immune system initiates and controls inflammation. We will evaluate biochemical processes involved in the chemotactic responses of polymorphonuclear leukocytes (PMNs), monocytes, and macrophages. We will characterize receptors for chemotactic factors on leukocytes and define the nature of the transductional events which follow occupancy of the receptor and lead to directed migration. We will also see if abnormalities of chemotactic factor receptors are associated with inflammatory diseases such as periodontal disease. We previously showed that transmethylation reactions mediated by S-adenosylmethionine are required for chemotaxis and that chemotactic factors alter the methylation of phospholipids. We recently found that the state of microtubule assembly affects cellular phospholipid methylation. Alterations in phospholipids following binding of chemotactic factors may produce biophysical changes in the cell membrane which are necessary for chemotaxis. Using models for studying chemotaxis in vitro, we will determine how chemotactic factors induce changes in the cellular phospholipid composition and what role such changes play in cellular orientation. We recently defined a model for the study of a partially uncoupled receptor involved in chemotaxis. Equine PMNs have a high affinity receptor for N-formylated chemotactic peptides (NFP) but do not orient nor migrate directionally towards the NFP. They do, however, orient and migrate to C5a. Interestingly, Equine PMNs do secrete lysosomal enzymes and produce superoxide in response to the NFP. Using this model we will study the nature of the defect in horse PMNs. With the binding assays we have developed, we will study PMNs from patients with juvenile periodontosis to see if the chemotactic defects in patients are due to abnormalities of chemotactic factor receptors. We will continue studying the effects of endotoxin on the function of macrophages from normally susceptible and resistant mice. We will determine how "priming" of normal mice with endotoxin renders them resistant to the leukopenic and anti-inflammatory effects of endotoxin. In sum, we will better elucidate biochemical mechanisms of inflammation as well as their control and characterize the factors which govern the effectiveness and intensity of inflammatory reactions.